DESCRIPTION: Plasmodium falciparum is the most virulent human malaria parasite, and its ability to evade host immune attack leads to persistent clinical infection. Its virulence and host immune evasion are mediated by a parasite-encoded protein, PfEMP- 1, exported and targeted to the erythrocyte surface. Despite its central roll in parasite pathogenesis and host immunity, the cellular dynamics of the export of PfEMP-l from the parasite to the erythrocyte surface is poorly understood. The proposed study will search for and define elements required for PfEMP-1 export. A model system comprised of two parasites clones, a non-cytoadherent one that does not express PfEMP-l on the infected erythrocyte surface and its cytoadherent parent that does express this antigen on the surface, has been established to allow comparative studies to define the elements responsible for these distinctive phenotypes. DNA micro array technology will be applied to determine differential expression within this clone pair at the level of gene transcription. In concert with this technology, proteomic analyses will provide differential expression at the level of translation and post-translational modifications. The differentially expressed genes/gene products will be further characterized to determine their spatial association with PfEMP-l and erythrocyte compartments. Their requirement in PfEMP-l export/targeting and cytoadherence will be assessed by gene knockout and complementation studies. A long-term goal is to elucidate the extra-parasite protein exporting mechanism and characterize the exporting machinery and to better understand the fundamental cellular processes underlying pathogenesis and immunity. Moreover, since the exporting and targeting process is unique to the parasite it also represents an attractive target for novel chemotherapy.